Transmission of Synovial Sarcoma from A Single Multiorgan Donor to Three Transplant Recipients: Cases Report and Literature Review

Background Donor-derived malignancy is sometimes unidentied at the time of transplantation, resulting in unanticipated donor-derived malignancy, which becomes a notable problem since the increasing use of marginal donors. Case presentation We rst report three cases of donor-derived synovial sarcoma from a single multiorgan donor in China. The donor was died of respiratory failure caused by an intrathoracic tumor, which was diagnosed as a benign tumor at the time of donation. All of the three recipients developed synovial sarcoma within 3 months to 13 months after transplantation, proven to be donor-derived. Liver transplant recipient died of tumor metastasis. Two kidney transplant recipients survived from metastases by comprehensive therapy, including the rst use of Anlotinib, exhibiting an effective anti-tumor activity. Conclusions This report highlights the importance of detailed donor assessment, close follow-up and timely treatment, as well as the need for establishing a post-transplant surveillance system for donor-derived transmission events. Whether to use organs from a donor with initial diagnosis of benign tumor needs to be cautious. Malignant potential of tumors needs to be excluded before transplantation, otherwise, the organs should be discarded.


Background
The persistent organ shortage requires the maximum utilization of all available donors, including those with tumors, that may lead to donor-derived malignancy [1][2][3] . There is a consensus that whether to use donor organs with tumors depends on risk levels of tumor transmission. However, a donor-derived malignancy is sometimes unidenti ed at the time of transplantation, resulting in unanticipated donorderived malignancy. Here, we rst report three cases of donor-derived synovial sarcoma from a single multiorgan donor in China. In addition, risk of using organ donor with benign tumor is further discussed to help improving the safety of transplantation.

Transplant recipients
In 2018, three recipients from a single multiorgan donor developed allograft synovial sarcoma within 3 months to 13 months consecutively after organ transplantation. Timeline was displayed in Fig. 1.
Synovial sarcoma was initially developed in allograft liver of recipient 1 three months after transplantation, who was a 26-year-old female with primary liver cancer. However, the donor-derived transmission was not recognized. The patient received a resection of left lateral lobe of allograft liver.
Recurrence in her right lobe of allograft liver was found 11 months after partial allograft hepatectomy.
3 months later, systemic metastases were found and she died within 2 months. Recipient 2 was a 43-year-old male who received the left kidney. 9 months after transplantation, multiple neoplasms in the allograft kidney were found by ultrasound and computed tomography (CT) scan.
Positron emission tomography with computed tomography (PET/CT) revealed a tendency to malignancy, without metastasis. Synovial sarcoma was identi ed after biopsy and the patient received allograft nephrectomy, followed by withdrawal of immunosuppression. The cancer was nally proven to be donorderived by DNA microsatellite. 4 months after nephrectomy, CT examination revealed diffuse pulmonary metastases. He received targeted therapy with Anlotinib, which exhibited an effective anti-tumor activity with the elimination of metastases. The patient was alive without cancer progression during two-year follow-up.
With the warning of transmission from the same donor, a regular cancer screening was performed for recipient 3 who was a 33-year-old male and received the right kidney. Unfortunately, he developed a single neoplasm in the allograft kidney 3 months after the warning. Biopsy pathology revealed the same result with recipient 2. He initially received radiofrequency ablation in order to preserve the allograft function.
However, local recurrence was found 6 months later. The patient received allograft nephrectomy, followed by withdrawal of immunosuppression. Donor-derived malignancy was proven by DNA microsatellite. Half a month later, CT examination revealed diffuse pulmonary metastases and he received targeted therapy with Anlotinib, which again exhibited an excellent e cacy. The patient was alive without cancer progression during almost two-year follow-up.

Organ donor
The donor was a 14-year-old girl who developed a 11 cm intrathoracic tumor. In October 2017, she died of respiratory failure caused by tracheal compression and donated a liver and two kidneys. Hematoxylin and eosin (HE) staining by biopsy before organ procurement revealed a benign tumor. Immunohistochemical staining revealed solitary brous tumor.

Imageological nding
Multiple solid hypo-echo neoplasms were found with punctiform blood ow signal inside the allograft kidney in recipient 2 ( Fig. 2A), as well as in recipient 3 (Fig. 2E), by color Doppler ultrasound. Compared with the density of allograft, a slightly higher density of neoplasm was found in non-enhancing CT, but a slow and relatively homogeneous enhancement with lower density inside the neoplasm was found in enhanced multiphase images in both recipient 2 ( Fig. 2B-D) and recipient 3 ( Fig. 2F-H). There was no evidence of metastases on CT examination.

DNA microsatellite
The length of detection locus in different tissues was shown in Fig. 4. Amel loci exhibited a female gender in both allograft and cancer tissues, con rming the donor-derived transmission.

Discussion And Conclusion
Transplantation from a donor with malignancy could produce a valuable increase in organs with a reasonable value of safety 4,5 . The reported risk of transmission varied from 0.01 to 0.05% 4-6 . Despite of a low risk, it has been intermittently reported, resulting in fatal consequences 1-3, 7,8 . This was the rst reported synovial sarcoma transmission through a multiorgan procedure from 1 donor to 3 recipients.
The identi cation of synovial sarcoma remained a challenge due to histological overlap with other tumor types, mainly based upon a combination of traditional morphology, identi cation of the chromosomal t(X;18) translocation and a panel of immunohistochemical markers 9 . Due to the limitation of diagnostic capacity or emergency of donation, misdiagnosis of malignancy before organ procurement might directly result in the use of malignant donor organs. In this study, synovial sarcoma was unidenti ed at the time of donation, leading to the subsequent unanticipated donor-derived transmission, that indicated the importance of systemic donor assessment. Due to the unrecognizability of some uncommon tumors or malignant potential, whether to use organs from a donor with initial diagnosis of benign tumor needs to be cautious. A list of benign tumors with malignant potential or other factors related to organ transplantation was summarized in Table 1. Donors with these tumors were recommended to receive a more detailed assessment to exclude malignant potential, otherwise, these donors should be discarded.
It remained speculative regarding the donor-derived transmission of malignancy from the donor without any signs of metastasis. Micro-metastasis of malignancy was considered as one hypothesis. Previous study demonstrated a greater risk for metastases of larger synovial sarcoma 10 . Given the tumor size of donor in this study, micro-metastasis was considered to be existing before organ procurement procedure.
Another hypothesis was that changes of immune system in cancer surveillance might promote development of malignancy, due to the use of immunosuppressant [11][12][13] . On this account, the synovial sarcoma grew faster after organ transplantation.
In this study, all recipients eventually developed synovial sarcoma, revealing a high transmission rate.
Previous study suggested that timely removal of allograft might be bene cial to prevent the development of metastasis 2 . In order to prevent transmission, it should be considered in all recipients after noti cation of cancer transmission in one recipient from a multiorgan donor. In this study, if the donor-derived transmission was recognized and warned earlier, we might prevent the transmission events by earlier removing the allograft.
Synovial sarcoma was considered an aggressive sarcoma, noted for its propensity of local recurrence and metastasis, with a poor prognosis owing to its resistance to radiation and chemotherapy. The treatment of allograft synovial sarcoma was rarely reported. However, several therapeutic options for allograft renal mass were listed, including partial nephrectomy, transplant nephrectomy, radiofrequency ablation and cryoablation, followed by altered or withdraw of immunosuppression 14 . Numbers of transplant surgeons and urologists faced with dilemma that required maximizing preservation of renal function while ensuring adequate cancer control. This study suggested that compared with local therapy, allograft nephrectomy followed by withdrawal of immunosuppression might be the best therapeutic option and more bene cial to local recurrence, which was supported by previous study 3 . Nevertheless, it did not prevent the development of metastasis, probably owing to the above-mentioned delayed treatment. Anlotinib was a new oral tyrosine kinase inhibitor, designed to primarily inhibit multi-targets in vasculogenesis and angiogenesis, which exhibited direct anti-tumor activity towards synovial sarcoma 15 . In this study, Anlotinib was proved to be effective towards synovial sarcoma by the elimination of metastases and prolonged progression-free survival of two kidney transplant recipients. Further observation of e cacy, drug resistance and safety were needed.
Donor-derived transmission of malignancy is not merely case report, but a notable public problem, which is considered to be underestimated, deserving much attention. This report highlights the importance of detailed donor assessment for preventing donor-derived malignancy, as well as the need for establishing a post-transplant surveillance system specially for donor-derived transmission events in the current era of deceased donor organ transplantation. Whether to use organs from a donor with initial diagnosis of benign tumor needs to be cautious. Malignant potential of tumors needs to be excluded before transplantation, otherwise, the organs should be discarded. Timely removal of allograft is the best option to prevent and cure donor-derived cancer transmission that should be considered in all recipients after noti cation of transmission in one recipient from a multiorgan donor.
Besides, Anlotinib is proved to be effective towards synovial sarcoma. waived that the information was anonymized and the submission did not include images that might identify the person.

Consent for publication
Consent for publication was waived that the information was anonymized and the submission did not include images that might identify the person.